A multicenter, open label, two cohort, single arm, phase II study to evaluate the efficacy and safety of the anti-TROP2 antibody-drug conjugate sacituzumab govitecan in patients with advanced differentiated and anaplastic thyroid neoplasms.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Tumores Neuroendocrinos

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hormonal diseases [C19]

Trial duration

30 Jul 2024 → ongoing

Decision date (initial)

2024-02-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Efficacy

The main hypothesis is that treatment with sacituzumab govitecan, a anti-Trophoblast cell surface antigen 2 (TROP-2), could be an effective treatment option for patients with either differentiated and anaplastic thyroid neoplasms because TROP-2 is highly expressed at the membrane of DTC and ATC.
The primary aim of this study is to seek for activity of a novel drug and mechanism of action in order to provide an additional line of treatment for thyroid neoplasms. Concisely, the study will assess the efficacy and safety of the anti-TROP-2 antibody-drug conjugate sacituzumab govitecan for differentiated and anaplastic thyroid neoplasms using objective response rate (ORR) as primary endpoint surrogate of efficacy.

Secondary objectives 4

1. To determine clinical outcomes such as disease control rate (DCR), duration of response (DoR), progression free survival (PFS) and overall survival (OS) of sacituzumab govitecan for differentiated and anaplastic thyroid neoplasms.
2. To determine the correlation of risk factors in the efficacy of sacituzumab govitecan for differentiated and anaplastic thyroid neoplasms.
3. To determine the correlation between TROP-2 expression levels at baseline and the efficacy of sacituzumab govitecan for differentiated and anaplastic thyroid neoplasms.
4. To determine the correlation between pathology-specific genetic alterations (i.e. TP53, TERT, BRAF or RAS mutations; NTRK and ALK rearrangements; RET fusions) at baseline, and the levels of TROP-2 and the efficacy of sacituzumab govitecan for differentiated and anaplastic thyroid neoplasms.

Conditions and MedDRA coding

Thyroid neoplasms: ● Cohort 1: Advanced radioactive-iodine refractory Differentiated Thyroid Carcinoma (DTC) ● Cohort 2: Advanced Anaplastic Thyroid Carcinoma (ATC).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent.
2. Patient is ≥ 18 years of age.
3. Patient has histologically confirmed metastatic or locally advanced unresectable radioactive-iodine refractory differentiated thyroid cancer (cohort A) or anaplastic thyroid carcinoma (cohort B).
4. Prior therapy in each cohort: a. Cohort A: Patients must have experienced progression on at least one previous treatment line with approved systemic therapies (Sorafenib, Lenvatinib or Cabozantinib) and a maximum of 3 prior systemic therapies. b. Cohort B: Patients should be included in first-line setting or after failure of any systemic therapy (up to 1 prior treatment lines).
5. Patient has radiographically documented and measurable metastatic or locally advanced disease at baseline.
6. An archival tumor tissue sample should be available for submission to the central laboratory for translational studies. If an archival tumor tissue sample is not available, a new biopsy tissue sample should be provided. No central pathological review will be needed to include the patient in the trial.
7. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. The following baseline laboratory data without transfusional support: a. Neutrophil count (ANC) ≥ 1,500/mm 3 . b. Platelet count ≥ 100 × 10 9 /L. c. Hemoglobin ≥ 9 g/dL. d. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN). Note: patients with Gilbert’s disease are excluded. e. Serum albumin > 3 g/dL. f. Creatinine clearance (CrCl) ≥ 60 mL/min as estimated by the Cockroft-Gault formula or as measured by 24 hour urine collection (GFR can also be used instead of CrCl) (see Table 10 for Cockcroft-Gault formula). GETNE T2318 - Protocol Version - 1.1 5 MAY 2023 Page 13/126 SETHY g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 xULN for patients with liver metastases.
9. Female patients must either: a. Be of nonchildbearing potential: i. Postmenopausal *(defined as at least 1 year without any menses) prior to screening , or ii. Documented surgically sterile (e.g.hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or bilateral tubal occlusion). *Those who are amenorrheic due to an alternative medical cause are not considered postmenopausal and must follow the criteria for childbearing potential subjects. OR b. If of childbearing potential: i. Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration, ii. And have a negative urine or serum pregnancy test within 7 days prior to Day 1 (females with false positive results and documented verification of negative pregnancy status are eligible for participation), iii. And if heterosexually active, agree to abstinence (if in line with the usual preferred lifestyle of the patient) or consistently use a condom plus 1 form of highly effective birth control (Appendix 4) per locally accepted standards starting at screening and throughout the study period and for at least 6 months after the final study drug administration.
10. Female patients must agree not to breastfeed or donate ovules starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
11. Male patients must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
12. Male patients with a partner with childbearing potential, or who is pregnant or breastfeeding must agree to abstinence or use a condom plus 1 form of highly effective birth control throughout the study period and for at least 6 months after the final study drug administration.
13. Patient agrees not to participate in another interventional study while on treatment in the present study.

Exclusion criteria 15

1. Patient has central nervous system (CNS) metastases.
2. Patient has ongoing clinically significant toxicity (Grade 2 or higher with the exception of neuropathy and alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery). Note: if patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
3. Patient has a history of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Note: Patients with non melanoma skin cancer, curatively treated localized prostate cancer, or carcinoma in situ of any type (if complete resection was performed) are allowed.
4. Patient has known active Hepatitis B or active hepatitis C: a. Patients who test positive for hepatitis B surface antigen (HBsAg). Patients who test positive for hepatitis B core antibody (anti-HBc) will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease. b. Patients who test positive for HCV antibody. Patients who test positive for HCV antibody will require HCV RNA by quantitative PCR for confirmation of active disease. Patients with a known history of HCV or a positive HCV antibody test will not require a HCV antibody at screening and will only require HCV RNA by quantitative PCR for confirmation of active disease. c. Patients who test positive for HIV antibody.
5. Patient has a known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2) with detectable viral load OR taking medications that may interfere with SN-38 metabolism.
6. Patient has documented history of a cerebral vascular event (stroke or transient ischemic attack), , or the following criteria for cardiac disease: a. Myocardial infarction or unstable angina pectoris within 6 months of enrollment. b. History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation. c. New York Heart Association (NYHA) class III or greater congestive heart failure or left ventricular ejection fraction of < 40%..
7. Known history of clinically significant active COPD, or other moderate-to-severe chronic respiratory illness present within 6 months prior to the first dose of study drug.
8. Patients with active chronic inflammatory bowel disease (ulcerative colitis, Crohn disease) and patients with a history of gastrointestinal obstruction or perforation within 6 months of enrollment.
9. Patient has uncontrolled hypertension or diabetes.
10. Patient has radiotherapy or major surgery within 4 weeks prior to the first dose of study drug.
11. Patients has received a live vaccine within 30 days, or antibiotics within one week prior to the first dose of study drug.
12. Patient has had chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to the first dose of study drug. Note: Patients participating in observational studies are eligible.
13. Patient has previously received topoisomerase 1 inhibitors.
14. Patient has known hypersensitivity to sacituzumab govitecan or to any excipient contained in the drug formulation.
15. Patient has other underlying medical conditions that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned treatment and follow-up.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be objective response rate (ORR), defined as the percentage/proportion of patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study period. Objective responses will be assessed locally by the investigator according to RECIST, version 1.1 (Appendix 3), and indicating the change in size of tumors as compared with baseline, at the first dose of study treatment.

Secondary endpoints 3

1. Efficacy secondary endpoints will be analyzed per cohort: ● Disease control rate (DCR). ● Duration of the response (DoR). ● Progression free survival (PFS). ● Overall survival (OS). ● Efficacy variables will be reported for subgroups to find potential correlation between patient characteristics (i.e. age, gender, ECOG, AJCC stage, differentiation, or previous treatments) and the clinical outcomes to sacituzumab govitecan.
2. Secondary safety endpoints: ● Frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0. ● Frequency of AEs leading to treatment discontinuation. ● Health-related quality of life (HRQoL), assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) version 3.
3. Secondary exploratory endpoints: ● Correlation of TROP-2 expression levels with efficacy endpoints (i.e. ORR, PFS, OS). ● Correlation of tumor genetic alterations with efficacy endpoints (i.e. ORR, PFS, OS).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Tumores Neuroendocrinos

Sponsor organisation

Grupo Espanol De Tumores Neuroendocrinos

Address

Calle De Velazquez 7 Planta 3

City

Madrid

Postcode

28001

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Tumores Neuroendocrinos

Contact name

GETNE

Public contact point

Organisation

Grupo Espanol De Tumores Neuroendocrinos

Contact name

MFAR clinical research

Third parties 1

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications